In This Issue Cite This: ACS Med. Chem. Lett. 2018, 9, 576−576
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IMAGING MASS SPECTROMETRY VISUALIZATION OF UNLABELED PEPTIDES AND SMALL MOLECULES Matrix-assisted laser desorption ionization time-of-flight imaging mass spectrometry (MALDI-TOF) is a novel tool to visualize penetration of small molecules in biological samples. This technique depends on the mass-to-charge ratios (m/z) of samples, which eliminates the need for a chemical label for visualization. MALDI-TOF imaging mass spectrometry of cancer cell lines requires the generation of 3D cell culture spheroids; however, not all cancer cells are amenable to growing uniform spheroids and/or with diameters large enough to facilitate imaging. In this issue, Moore and colleagues (DOI: 10.1021/ acsmedchemlett.8b00091) present in their Technology Note the application of MALDI-TOF imaging mass spectrometry to visualize unlabeled peptides and small molecules in tumor explants. Since tumor explants can be divided into the desired size, the size limitation of 3D spheroids is eliminated. The authors performed proof-of-concept studies on breast tumor explants with the known peptide drug cyclosporine A, the small molecule drug 4-hydroxytamoxifen, and their previously reported peptide chemical probe SRC2-SP4. This work paves the way for the application of this method to other tumor types or patient-derived xenografts.
was selected for further evaluation and demonstrated favorable absorption and riluzole formation in both rats and mice. The compound also inhibited melanoma tumor growth in mice. Administration of riluzole as a prodrug may therefore mitigate variable exposure currently observed in humans.
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NATURAL PRODUCT ANALOGUES DEMONSTRATE ANTIBIOFILM ACTIVITY AND ABILITY TO INCREASE POTENCY OF THE ANTIBIOTIC COLISTIN Multidrug resistant bacterial infections are becoming an increasing health threat due to a reduction in antibiotic development over the past 30 years. Of particular concern are bacterial biofilms and antibiotic-resistant strains since these are particularly challenging to treat. An alternative approach to a new antibiotic discovery is to enhance the activity of current antibiotics through adjuvants. In the present issue, Melander and colleagues (DOI: 10.1021/ acsmedchemlett.8b00161) describe their antibiotic adjuvant approach using a family of marine natural products called meridianins and their analogues. The authors synthesized Meridianin D and various derivatives and evaluated their ability to prevent biofilm formation and to disperse preformed biofilms of methicillin-resistant S. aureus (MRSA), which led to the identification of several active compounds. Additionally, the authors found that meridianin analogues mitigate resistance to the antibiotic colistin in several Gram-negative bacterial strains. Ongoing efforts include mechanistic studies and further structural modifications to enhance the activity of the identified compounds.
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DIPEPTIDE PRODRUGS OF THE GLUTAMATE MODULATOR RILUZOLE Riluzole is an FDA-approved drug for the treatment of amyotrophic lateral sclerosis (ALS) and also inhibits growth of melanoma cells that express the type 1 metabotropic glutamate receptor (GRM1). Metabolism of riluzole by the variably expressed liver isozyme CYP1A2 via oxidation of the exocyclic amine leads to highly variable exposure upon oral administration in humans. In order to address the variability of exposure, Pelletier et al. (DOI: 10.1021/acsmedchemlett.8b00189) developed prodrugs of riluzole by masking the exocyclic amine with peptide conjugates. Cleavage by blood peptidases would then release riluzole. The authors prepared a series of natural and unnatural dipeptide prodrugs and tested these for their ability to resist cleavage prior to absorption from the GI tract and to form riluzole in serum. N-t-Butylglycylsarcosylriluzole (FC-3423) © 2018 American Chemical Society
Published: July 12, 2018 576
DOI: 10.1021/acsmedchemlett.8b00299 ACS Med. Chem. Lett. 2018, 9, 576−576
